Glycidamides for inducing a hypnotic response

ABSTRACT

2-Phenylglycidamides such as 3-chloro-2-(2,4-dichlorophenyl) glycidamide, are described. The compounds have utility in the polymer field and also possess useful biological activity.

United States Patent [191 [111 3,741,191 Quick June 26, 1973 GLYCIDAMIDES FOR INDUCING A [56] References Cited HYPNOTIC RESPONSE OTHER PUBLICATIONS [75] Inventor Carolyn Quick Mameca Cam Murray et al., J. Am. Chem. Soc., Vol. 56, No. 12, De- 73 Assignee: Shell on Company, New York, NY. cember, 1934, pp 2749-2751- [22] Flled: 1971 7 Primary Examiner-Jerome D. Goldberg [21] Appl. No.: 187,882 Attorney-Frank R. La Fontaine et a].

Related US. Application Data [62] Division of Ser. No. 5,109, Jan. 22, 1970, Pat. No. [571 ABSTRACT 2-Phenylglycidamides such as 3-chloro-2-(2,4- dichlorophenyl) glycidamide, are described. The com- U-S. Cl. pounds have in the polymer and also p03- Intsess useful biological activity [58] Field of Search 424/278 4 Claims, No Drawings 1 GLYCIDAMIDES FOR INDUCING A HYPNOTIC RESPONSE This is a division 'of application Ser. No. 5,109 filed Jan. 22, 1970, now US. Pat. No. 3,646,21 I.

BACKGROUND OF THE INVENTION 1. Field of the Invention Thisinvention is directed to novel compounds containing an oxirane ring. More particularly, the invention relates to certain novel and useful 2- phenylglycidamides.

2. Description ofthe Prior Art While substituted glycidamides have been known for many years, relatively few Z-phenylglycidamicles have been reported in the literature. As far as is known only 3-methyl-2-phenylglycidamide and 2,3- diphenylglycidamide have thus far been reported (Murray et al., J. Am. Chem. Soc, 56, 2749 (1934)).

SUMMARY OF THE INVENTION It is an object of this invention to provide novel and useful 2-phenylglycidamides. It is another object to provide novel Z-phenylglycidamides possessing utility in the polymer field and having activity as nervous system depressants. Accordingly, this invention is a novel class of 2-phenylglycidamides.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The novel class of compounds of this invention can be described by the formula N-ti C=O Y NH: (I)

wherein X is hydrogen or halogen, Y is hydrogen, halogen or alkyl of 1-4 carbon atoms, Z is halogen, nitro, alkyl of 1-4 carbon atoms, trifluoromethyl or alkylsulfonyl of l-4 carbon atoms, H is hydrogen and n is l, 2, or 3, with the provisos that when n is less than 3, each Z may be the same or different and when Y is alkyl, X is hydrogen.

The alkyl moieties may be straight or branched-chain and include methyl, ethyl, isopropyl, butyl and the like.

The halogens are fluorine, chlorine, bromine and iodine.

Mainly because of availability of the starting materials and ease of synthesis the Z-phenylglycidamides of the following formula form a preferred subclass:

wherein R is chlorine, bromine or hydrogen; R is chlorine, bromine, hydrogen or alkyl of l-4 carbon atoms and R R and R which may be the same or different, are fluorine, chlorine, bromine, hydrogen, trifluoromethyl or alkyl of l-4 carbon atoms; with the provisos that at least one ofR- and R is chlorine or bromine and that when R, is alkyl, R is hydrogen.

The alkyl moieties may be straight or branched-chain and include methyl, ethyl, isopropyl, butyl and the like.

Exemplary compounds within this subclass include: when R, is chlorine or bromine; 3-chloro-2-(2-chlorophenyl)glycidamide, 3,3-dichloro-2-(2,3-dichlorophenyl)glycidamide, 3-bromo-2-(2,3-dichloro-4- propylphenyl)glycidamide, 3-ethyl-2-(2-chloro-3,4-difluorophenyl)glycidamide, 2-(2-bromo-4-ethylphenyl)glycidamide, 2-(2-chloro-3-methylphenyl)glycidamide, 2-(2,3-dichloro-4-fluorophenyl)glycidamide, 3-chloro-3-bromo-2-(2-chloro-4- propylphenyl)glycidamide, 2-(2-chlorophenyl)glycidamide, 3-methyl-2-(2-chloro-3-methylphenyl)glycidamide, 3-chloro-2-(2-chloro-3,4-dimethylphenyl)glycidamide, 2-(2-chloro-4-trifluoromethylphenyl)glycidamide, 3-chloro-2-(2-chloro-3-trifluoromethylphenyl)- glycidamide and the like;

when R, is chlorine or bromine;

2-(4-chlorophenyl)glycidamide,

2-( 3,4-dichlorophenyl )glycidamide,

3-chloro-2-(4-bromophenyl)glycidamide,

3,3-dichloro-2-(2-methyl-4- chlorophenyl)glycidamide, 3-ethyl-2-( 2-methyl-3,4-

dichlorophenyl)glycidamide, I 3-bromo-2-(3,4-dichlorophenyl)glycidamide, 3-chloro-2-(2-butyl-3,4-

dichlorophenyl)glycidamide, 3-chloro-2-(2-fluoro-4bromophenyl)glycidamide, 3-chloro-2-(2,3-difluoro-4- chlorophenyl)glycidamide, 3-chloro-2-(2,3-dimethyl-4- chlorophenyl)glycidamide,

3-chloro-2-( 3-ethyl-4-bromophenyl )glycidamide,

3-bromo-2-(2-fluoro-3-methyl-4- chlorophenyl)glycidamide, 2-(2-trifluoromethyl-4-chlorophenyl)glycidamide, 3-chloro-2-(3-trifluoromethyl-4- chlorophenyl)glycidamide and the like;

and when R and R, are chlorine or bromine,

2-(2,4-dichlorophenyl)glycidamide,

2-( 2,3 ,4-trichlorophenyl )glycidamide,

2-( 3-methyl-2,4-dichlorophenyl )glycidamide,

3-chloro-2-(2,4-dibromphenyl)glycidamide,

3-chloro-2-(3-fluoro-2,4-

dichlorophenyl)glycidamide, 3,3-dichloro-2-(2,3,4-trichlorophenyl)glycidamide, 3-methyl-2-(2,4-dichlorophenyl)glycidamide, 3-butyl-2-(3-methyl-2,4-

dichlorophenyl)glycidamide, 2-(2,4-dichloro-3-trifluoromethylphenyl)glycidamide, 3-chloro-(2,4-dichloro-3-trifluoromethylphenyl)- glycidamide and the like.

Within the 2-phenylglycidamides of formula II, a particularly preferred subclass because of their activity as nervous system depressants, especially as sedatives, hypnotics and anticonvulsants, are those where R is hydrogen or chlorine, preferably hydrogen, R, is hydrogen, chlorine or bromine, preferably chlorine, R is chlorine or methyl, R is hydrogen or chlorine, preferably hydrogen, and R, is hydrogen, chlorine, fluorine or methyl, with the proviso that at least one of R and R is chlorine. This is the most preferred subclass of the compounds of the invention.

Preferred species are:

3-chloro'2-(2,4-dichlorophenyl)glycidamide 3 -chloro-2-( 2-chloro-4-fluorophenyl )glycidamide 3-chloro-2-( Z-chlorophenyl )glycidamide 3-bromo-2-(2,4-dichlorophenyl)glycidamide 3-chloro-2-(2-methyl-4-chlorophenyl)glycidamide 3-chloro-2-(2-chloro-4-methylphenyl)glycidamide 2-(2,4-dichlorophenyl)glycidamide 3,3-dichloro-2-(2,4-dichlorophenyl)glycidamide When the compounds of the invention contain different atoms substituted at the 3-position, i.e., X and Y are different, two stereoisomers can exist. It is to be understood that these isomers as well as mixtures of the two are within the scope of this invention.

The 2-phenylglycidamides of the invention find utility in the polymer field. For example, they are especially advantageous as modifiers of epoxy resins, particularly the glycidyl polyether resins such as are described and claimed in US. Pat. No. 2,633,458 with which they can be mixed in proportions of about 1:10 to 1:1 and cured in the usual way to obtain products of controlled properties, especially as regards flexibility. Those Z-phenylglycidamides containing halogen have the additional advantage of acting as fire-retardants when mixed with such epoxy resins and cured.

The most preferred subclass, as previously described, are particularly valuable as nervous system depressants, especially as hypnotics sedatives and anticonvulsants.

PREPARATION The Z-phenylglycidamides of this invention, except for those of formula I in which Y is alkyl of 1-4 carbon atoms, may be prepared by reaction of the appropriate a-(halomethyl)mandelamide with sodium hydroxide, sodium methoxide or sodium hydride. These a-(halomethyl)mandelamides, in turn, are readily prepared by the hydrolysis of the corresponding a-(halomethyl)mandelonitriles with 80-95% sulfuric acid at temperatures of from about 80l C, preferably about 95 C. The a-(halomethyl)mandelonitriles are prepared by the known method of reacting the corresponding 2-haloacetophenones with hydrogen cyanide in the presence of a small amount of potassium cyanide as catalyst.

The 2-haloacetophenones may be prepared by a variety of methods. Most may be prepared by the well known Friedel-Crafts acylation of the appropriately substituted benzene with acetyl chloride or the appropriate monoor dihaloacetyl chloride. The 2-position of the appropriately ring-substituted acetophenone may be halogenated to form the 2,2- dihaloacetophenones using the appropriate halogen in formic acid. The 2,2,2-trihaloacetophenones may be prepared by the free-radical halogenation of the appropriate 2,2-dihaloacetophenone.

The 3-alkyl substituted Z-phenylglycidamicle may be prepared by the alkaline peroxide oxidation of the appropriate ,G-alkylatroponitrile; these B-alkylatroponitriles, in turn, may be prepared by the base catalyzed condensation of the appropriate substituted benzylcyanide and aldehyde. These procedures are described more fully by Knowles et al., J. Am. Chem. 800., 54, 2028 (1932) and Vigier et al, Bull. Soc. Chim. France, 677 (1963).

As previously mentioned, those 2- phenylglycidamides substituted by two different atoms at the 3-position are capable of existing in two geometrically isomeric forms. For purposes of this invention those isomeric pairs that were separated have been designated as either a or B. The B isomers were those that were the major component of the isomeric pair, generally were the lower melting, and had the longer chromatographic retention times on silica gel G. The a isomers conversely were the minor component of the isomeric pair and had shorter chromatographic retention times. The a isomers also tended to be more unstable relative to the B isomer of the pair. The stereochemical configuration of the a and B isomers were not determined.

The following examples are illustrative of the methods used to prepare the compounds of this invention. In these examples, parts" means parts by weight unless otherwise expressly indicated, and parts by weight bear the same relationship to parts by volume as does the kilogram to the liter. All elemental analyses are based on percent by weight.

EXAMPLE 1. PREPARATION OF HALOACETOPHENONES a. 2,2,2',4,5-Pentachloroacetophenone with 1N hydrochloric acid, 5% aqueous sodium bicar-' bonate, saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. Stripping of the solvent afforded 309 parts crude brown liquid which upon distillation gave 264 parts (76%) light yellow, 2,2,2',4,5'-pentachloroacetophenone, b.p. l l7- 123 C at 0.7 mm. The product was identified by infra red spectral analysis.

Cl Anal. Calcd for c,r-1,ct,o 60.7 Found 61.3

b. 2,2,2-Trichloroacetophenone Chlorine gas was bubbled into a stirred solution of 68 parts 2'-chloroacetophenone in 240 parts by volume glacial formic acid at 30 C containing a small amount of dissolved hydrogen chloride. The reaction was continued for 4 hours while the temperature slowly rose to 50 C. After standing overnight the reaction mixture was poured into water and the product was extracted with methylene chloride. The extracts were washed with 5% sodium bicarbonate solution and water, and dried with anhydrous magnesium sulfate. Solvent removal afforded 96 parts (98%) of slightly yellow liquid, 2,2,2-trichloroacetophenone. The product was identified by infrared spectral analysis.

c. 2,2,2,2,4'-Pentachloroacetophenone Chlorine gas was slowly added over 30 hrs. with stirring to 307 parts 2,2,2',4-tetrachloroacetophenone undergoing ultraviolet irradiation. The reaction temperature was maintained at l55l60 C. The product was stripped under high vacuum to give 347 parts (100%) of the yellow liquid, 2,2,2,2',4'- pentachloroacetophenone. The product was identified by infrared spectral analysis.

C1 Anal. Calcd for CuHnClsO 60.7 Found 61.2

EXAMPLE 2. 3-Chloro-2-(2,4-dichlorophenyl)glycidamide (a and ,3

isomers) a. 2,4-Dichloro-a-(dichloromethyl)mandelonitrilc 2,2,2,4'-Tetrachloroacetophenone (202 parts) obtained by the usual Friedel-Crafts reaction from mdichlorobenzene and dichloroacetyl chloride dissolved in 80 parts by volume of liquid hydrogen cyanide at C was treated with 15 drops of a freshly prepared potassium cyanide solution. A vigorous exothermic reaction occurred causing reflux of the hydrogen cyanide. After 15 minutes refluxing, 100 parts by volume of ether and 4 parts by volume of concentrated sulfuric acid were added. The ether and excess hydrogen cyanide were removed by distillation and the resultant solid was recrystallized from hexanezbenzene (19:1) to give 187 parts of 2,4-dichloro a-(dichloromethyl)mandelonitrile as a white solid melting at 93-95 C, identified by elemental analysis.

N Cl Anal. Calc'd for NOCLC H 4.9 49.8 Found 5.2 50.0

b. The nitrile from (a) above (300 parts) in 1,000 parts by volume of 80% sulfuric acid was heated on a steam bath for 16 hours, cooled and poured over ice. The resultant gummy precipitate was dissolved in methylene chloride, dried and cooled to give 258 parts of 2,4-dichloro-a-(dichloromethyl)mandelamide melting at 135-l37 C. This was identified by infrared spectral analysis.

c. To a stirred suspension of 2.4 parts of hexanewashed 50% sodium hydride-mineral oil suspension in 50 parts by volume anhydrous tetrahydrofuran was added all at once a solution of 15 parts of the amide from (b) above in 100 parts by volume of anhydrous tetrahydrofuran. An exothermic reaction occurred with hydrogen evolution and the formation of a white precipitate. The reaction mixture was stirred for 6 hours, poured into water, and extracted with ether. The ether extracts were washed with water, dried with anhydrous magnesium sulfate and the solvent was removed to afford a yellow viscous liquid. Recrystallization from methylene chloride/hexane gave 6 parts white crystals, m.p. ll5-l 2 1 C, containing a mixture of two isomers in a 6:1 ratio. Chromatographic separation of the mixture followed by recrystallization gave 3.1 parts of the ,B isomer (melting at l22-123 C) and 0.4 parts of the a isomer (melting at 170-l71.5 C) of 3-chloro-2-(2,4- dichlorophenyl)glycidamide which were identified by elemental and infrared spectral analyses.

N Cl Analysis Calcd for NO CI C H 5.3 39.9 Found for lsomer (B) m.p. 122123 C 5.3 39.7 Found for lsomer (a; m.p. 170-17l.5C 5.3 39.7

d. To a stirred solution of 60.6 parts of the amide from (b) above in 175 parts by volume of anhydrous methanol was added dropwise a solution of 10.8 parts of sodium methoxide in 100 parts by volume of anhydrous methanol. The resulting solution was stirred at room temperature for 6 hours and allowed to stand overnight. The reaction mixture was poured into water and extracted with methylene chloride. The extracts were washed with water, dried with anhydrous magnesium sulfate and the solvent removed to afford a crude mixture of the two isomers as in method (c) above, which when chromatographed and recrystallized gave 34.3 parts of the B isomer, melting at l22l24 C and 1.7 parts of the a isomer melting at l69.5l C, which were identified by Nuclear Magnetic Resonance and infrared spectral analyses.

EXAMPLE 3. 2-( 2,4-Dichlorophenyl)-3-propylglycidamide N Anal. Calc'd for CygHuCigN 5.8 29.6 Found 5.6 28.5

b. A stirred mixture of 6.0 parts of the nitrile of (a) above, 5 parts by volume 30% hydrogen peroxide, 10 parts by volume sodium carbonate solution and 30 parts by volume acetone were heated at 52 C for 30 minutes. Cooling, filtration of the resultant white crystals and recrystallization from ethanol gave 3.5 parts of 2-(2,4-dichlorophenyl)-3- propylglycidamide, m.p. l6l162 C. The orig'inal filtrate afforded an additional 2.5 parts 2-(2,4- dichlorophenyl)-3-propylglycidamide, m.p. l60-l61 C from a hexane-benzene mixture. The total yield was 6.0 parts (88%).

Using the procedures of Examples 13 the following Z-phenyl-glycidamides were prepared. The results are summarized in Table l. The compounds are identified by the following formula:

TABLE 1 Elvnnnlnl analysis Compound 7.

1112112 5032 RG29 Elli Quinn 170g Burgh; v

:22.19:::aamamnmmmmmmmmmamamem A 2-Ol, 4-CH3 1 a and 8 mixture. 2 Crude liquidv NERVOUS SYSTEM DEPRESSANT ACTIVITY The hypnotic activity of these glycidamides was noted as follows. Mice were orally intubated with 500 mg/kg (mg/kg in these tests refers to milligrams of test compound per kilogram of animal body weight) of the test compound and observed at minutes, 1 hour, 2 hours, 4 hours and 24 hours. Pharmacotoxic signs, especially onset and termination of the loss of righting reflex, were noted. Any compound inducing a loss in the righting reflex in 50 percent of the mice at any of these test intervals was considered active and were tested at lower oral doses and/or by intraperitoneal injection. Two reference drugs, Glutethimide and sodium pentobarbital, were included in the tests as controls. The results of the tests are shown in Table 11.

Table 11 Oral Approx. Approx. Hypnotic Activity Test Lethal Hypnotic lntraperitoneal Compound Dose Dose Rating at 180 mg/kg mg/kg mg/kg 23 500 62 4 500 250 ++H- l7 500 500 +-ll- 21 500 500 -++--l'+ 24 ++l 25 29 500 inactive 30 500 250 31 1+ 32 500 inactive Glutethimide 560 180 +-l--"- Pentobarbital-Na 500 125 l. 2,8 refers to beta isomer prepared in Example 2; other numbers refer to compounds of Table l.

2. 1-2 mice, -+-l'= 3-6 mice, +H-= 7-9 mice and +-H-+= 10 mice out of 10 exhibited hypnotic activity.

3. at I00 mg/kg. not tested at I80 mg/kg.

4. All mice died.

5. 9 out of a total of 9 mice tested exhibited hypnotic response.

6. 2 out of a total of 5 mice tested exhibited hypnotic response.

7. Based on mean response of l 1 groups of 10 animals.

In addition to the hypnotic activity, compound 28 Found a oloxowocaw-owoowzcoooo &

eey-ap s-r oaw-swpwas also shown to exhibit other nervous system depressant effects. These include minor tranquilizing activity as shown by the pernicious preening test of Wilfon, J. G. et al., Fed. Proc., 19, 20 (1960); skeletal muscle relaxant activity as shown by antagonism to the lethal effect of intravenous injection of styrchnine sulfate; and, lastly, antagonism of supra-maximal electroshock seizure test of Swinyard, E. A., J. Am. Pharm. Assoc. 38, 201 (1949). The results of thest tests are shown in Table 111 in comparison with the reference compounds, Glutethimide and sodium pentobarbital. The data show that compound 23 is more active and also has a greater safety factor (i.e. the ratio of LB ED is larger) than the two reference compounds.

Compositions according to the present invention also comprise a pharmaceutical carrier which may either be solid material or a liquid. Preparations for oral adminis tration can be liquids or solids or any combination of these forms, such as syrups, elixirs, powders, capsules, or tablets. Preparations for administration of the active agent in unit dose form can be powders, compressed tablets, or a powder enclosed ina suitable capsule of absorbable material such as gelatin. The powders or compressed tablets may also comprise suitable excipients and/or diluents such as starch, lactose, stearic acid, magnesium stearate, dextrin or polyvinylpyrrolidone.

Preparations for parenteral administration may be sterile solutions or suspensions in liquids such as water, physiological saline, polyethylene glycol, mineral oil, ethyl oleate, methylcellulose, dimethyl sulfoxide or other liquid excipients known in the pharmaceutical and veterinary formulations art.

The unit dosage or therapeutically effective quantity of the glycidamides used according to this invention as analgesics, muscle relaxants, anticonvulsants and/or tranquilizers can vary over wide limits. For oral or parenteral administration is some cases, as little l0 milligrams of the active material per kilogram of body weight can be effective in the reduction of pain or in effecting sedation and muscle relaxation, while seldom will a dosage in excess of about 200 milligrams per kilogram of body weight be required. In general, for oral administration the effective dosage will be from about 10 wherein X is hydrogen or halogen, Y is hydrogen, halogen or alkyl of 1-4 carbon atoms, Z is halogen, 3-nitro, alkyl of 1-4 carbon atoms, trifluoromethyl or 4- alkylsulfonyl of l-4 carbon atoms, H is hydrogen and 15 to 200 milligrams per kilogram of body weight, 5 n is a whole number form one to three; with the proviwhile for parenteral administration, the effective dos- SOS h h i l h 3 h Z may b the Same age will be from about to about 100 milligrams per or diffe t and when Y is alkyl, X is hydrogen kilograms of body weight The yp dose for the 2. A method ofinducing a hypnotic response in mamoral route is about 40 milligrams P kilogram of mals comprising administering to a mammal in need of body W F P dose for the pars! 10 such treatment an effective dosage for inducing a hypteral route 1s 40 milligram per kilogram of mammal notic response of a compound of the formula body weight. Each dosage unit form-each capsule, tablet, ampoule, or prescribed dose can contain from about 1 percent to about 95 percent of active material, based upon the total weight of the formulation O R and preferably contains from about 2.5 percent to about 50 percent of the active material, on the same I 1 basis. Of course, it is possible to administer the thera- R R; I peutics without the use of a pharmaceutical carrier. NH:

The therapeutic agents used according to the invention can be administered either prior to or after the onset of the condition to be treated, such as when they wherein R is Chlorine, bromine or y g 1 is @1110- are used as: analgesics for the amelioration of pain; rifle, n hydrogen 0! alkyl Of l-4 Carbon atoms motor depressants or tranquilizers to relieve nervous and 2, 3 and 4, which y be the Same different, tensioru central depressants to reduce hyperexcitability are fluorine, chlorine, bromine, hydrogen, trifluoroand induce sedation; or as muscle relaxants for relief methyl or alkyl of l-4 carbon atoms; with the provisos from pain and discomfort of disorders involving muscle that at least one of R and R, is chlorine or bromine and spasms. that when R, is alkyl, R is hydrogen.

TABLE III Minor tranquilizing Antistrychnine Maximal electroactivity i.p. activity i.p., mgalkg. shock i.p., mgJkg.

EDm E13 0 E1350 L153; Test compound (mg./kg.) LDso/EDsO (mg-l g-) sol so g/kg.) Dso/EDao mgJkg.

2 36.5 14 24. 7 21 24. 7 21 510 Glutethimido 100 5. 6 75 7. 5 560 lentobarbitnl-Na 50 2. 3 3. 3 30 3. a 130 3. The method according to claim 2 wherein R is hy drogen or chlorine, R is hydrogen, chlorine or bromine, R is chlorine or methyl, R is hydrogen or chlorine, and R, is hydrogen, chlorine, fluorine or methyl;

with the proviso that at least one of R and R is chlorine.

4. The method according to claim 3 wherein R, R

and R are hydrogen and R and R are chlorine. 

2. A method of inducing a hypnotic response in mammals comprising administering to a mammal in need of such treatment an effective dosage for inducing a hypnotic response of a compound of the formula
 3. The method according to claim 2 wherein R is hydrogen or chlorine, R1 is hydrogen, chlorine or bromine, R2 is chlorine or methyl, R3 is hydrogen or chlorine, and R4 is hydrogen, chlorine, fluorine or methyl; with the proviso that at least one of R2 and R4 is chlorine.
 4. The method according to claim 3 wherein R, R1 and R3 are hydrogen and R2 and R4 are chlorine. 